Digestive enzymes are enzymes that can break down one or more components of foods, e.g., carbohydrates, lipids/fats, proteins, cellulose, nucleic acids, etc., and thereby assist in digestion and uptake of nutrients. Certain digestive enzymes are produced by the salivary glands, glands in the stomach, the pancreas, and glands in the small intestines. For example, digestive enzymes produced by the pancreas and secreted into the stomach and small intestine aid in digestion. Other digestive enzymes are produced by plants, fungi, or microorganisms (e.g., papain, bromelain).
Digestive enzymes have been administered to mammals to treat enzyme deficiencies caused by conditions affecting the pancreas, such as pancreatitis and pancreatic enzyme deficiency. Pancreatic enzymes administered to humans are commonly of porcine origin. Manufacturers of enzyme preparations have also used enteric coatings for lipase compositions in individuals with cystic fibrosis who require administration of lipases. The preparations for lipase delivery have used enteric coatings containing, for example, hypromellose phthalate, dimethicone 1000, and dibutyl phthalate.
Certain methods for coating sensitive bioactive substances such as enzymes have been described, see, e.g., U.S. Pat. No, RE40,059; 6,835,397; 6,797,291; 6,616,954; 6,312,741; 6,251,478; 6,153,236; 6,013,286, and 5,190,775, and Ser. No. 12/386,051, all of which are incorporated by reference in their entirety herein.
Influenza A (H1N1) virus is a subtype of influenza virus A and the most common cause of influenza (flu) in humans. Some strains of H1N1 are endemic in humans and cause a small fraction of all influenza-like illness and a large fraction of all seasonal influenza. H1N1 strains caused roughly half of all human flu infections in 2006. Other strains of H1N1 are endemic in pigs (swine influenza) and in birds (avian influenza).
In June 2009, WHO declared that flu due to a new strain of swine-origin H1N1 was responsible for the 2009 flu pandemic. This strain is commonly called “swine flu” by the public media.
Influenza A virus strains are categorized according to two proteins found on the surface of the virus: hemagglutinin (H) and neuraminidase (N). All influenza A viruses contain hemagglutinin and neuraminidase, but the structure of these proteins differ from strain to strain due to rapid genetic mutation in the viral genome. Influenza A virus strains are assigned an H number and an N number based on which forms of these two proteins the strain contains. There are 16 H and 9 N subtypes known in birds, but only H 1, 2 and 3, and N 1 and 2 are commonly found in humans.
The Spanish flu, also known as La Gripe Española, or La Pesadilla, was an unusually severe and deadly strain of avian influenza, a viral infectious disease, that killed some 50 million to 100 million people worldwide over about a year in 1918 and 1919. It is thought to be one of the most deadly pandemics in human history. Tt was caused by the H1N1 type of influenza virus. It is postulated that the Spanish flu caused an unusual number of deaths because it may have caused a cytokine storm in the body. The recent epidemic of bird flu, also an Influenza A virus, had a similar effect. The Spanish flu virus infected lung cells, leading to overstimulation of the immune system via release of cytokines into the lung tissue. This leads to extensive leukocyte migration towards the lungs, causing destruction of lung tissue and secretion of liquid into the organ, making it difficult for the patient to breathe. In contrast to other pandemics, which mostly kill the old and the very young, the 1918 pandemic killed unusual numbers of young adults, which may have been due to their healthy immune systems being able to mount a very strong and damaging response to the infection.
The more recent Russian flu was a 1977-1978 flu epidemic caused by strain Influenza A/USSR/90/77 (H1N1). It infected mostly children and young adults under 23 because a similar strain was prevalent in 1947-57, causing most adults to have substantial immunity. Some have called it a flu pandemic, but because it only affected the young it is not considered a true pandemic. The virus was included in the 1978-1979 influenza vaccine.
In the 2009 flu pandemic, the virus isolated from patients in the United States was found to be made up of genetic elements from four different flu viruses—North American Mexican influenza, North American avian influenza, human influenza, and swine influenza virus typically found in Asia and Europe. This strain appears to be a result of reassortment of human influenza and swine influenza viruses, in all four different strains of subtype H1N1.
Preliminary genetic characterization found that the hemagglutinin (HA) gene was similar to that of swine flu viruses present in U.S. pigs since 1999, but the neuraminidase (NA) and matrix protein (M) genes resembled versions present in European swine flu isolates. The six genes from American swine flu are themselves mixtures of swine flu, bird flu, and human flu viruses. While viruses with this genetic makeup had not previously been found to be circulating in humans or pigs, there is no formal national surveillance system to determine what viruses are circulating in pigs in the U.S.
On Jun. 11, 2009, the WHO declared an H1N1 pandemic, moving the alert level to phase 6, marking the first global pandemic since 1968.
Communicable diseases are currently the leading cause of preventable deaths worldwide, disproportionately affecting resource-poor settings. Pandemic influenzas add to already unacceptable levels of morbidity and mortality from diarrhea, malaria, pneumonia, malnutrition, HIV/AIDS and tuberculosis, in addition to causing high maternal and neonatal death rates. A few key conditions cause 90% of deaths from communicable diseases: pneumonia (3.9 million deaths per year); diarrhoeal diseases (1.8 million); and malaria (1.2 million). Malnutrition is a significant contributing factor to this mortality. During a pandemic, these illnesses are likely to increase in resource-poor settings where chronically strained health systems would face even higher patient volumes, severe resource constraints, and absenteeism of critical staff.
The current prophylactic means for preventing the flu is by Injectable Inactivated Vaccine or Nasal Spray Flu Vaccine. Commonly called the “flu shot”, the Injectable Inactivated Vaccine method employs an inactivated vaccine (containing killed virus) that is given with a needle, usually in the arm. The flu shot is approved for use in people older than 6 months, including healthy people and people with chronic medical conditions. Alternately, the nasal-spray flu vaccine—a vaccine made with live, weakened flu viruses that do not cause the flu (sometimes called LAIV for “live attenuated influenza vaccine” or FluMist®). LAIV (FluMist®) is approved for use in healthy people 2-49 years of age who are not pregnant.
Typically each vaccine contains three influenza viruses-one A (H3N2) virus, one A (H1N1) virus, and one B virus. The viruses in the vaccine change each year based on international surveillance and scientists' estimations about which types and strains of viruses will circulate in a given year. About 2 weeks after vaccination, antibodies that provide protection against influenza virus infection develop in the body.
Annual influenza vaccination is the most effective method for preventing influenza virus infection and its complications. Influenza vaccine can be administered to any person aged >6 months (who does not have contraindications to vaccination) to reduce the likelihood of becoming ill with influenza or of transmitting influenza to others. Trivalent inactivated influenza vaccine (TIV) can be used for any person aged >6 months, including those with high-risk conditions. Live, attenuated influenza vaccine (LAW) may be used for healthy, nonpregnant persons aged 2-49 years. If vaccine supply is limited, priority for vaccination is typically assigned to persons in specific groups and of specific ages who are, or are contacts of, persons at higher risk for influenza complications. Because the safety or effectiveness of LAIV has not been established in persons with underlying medical conditions that confer a higher risk for influenza complications, these persons should only be vaccinated with TIV. Influenza viruses undergo frequent antigenic change (i.e., antigenic drift), and persons recommended for vaccination must receive an annual vaccination against the influenza viruses forecasted to be in circulation. Although vaccination coverage has increased in recent years for many groups targeted for routine vaccination, coverage remains low among most of these groups.
Antiviral medications are an adjunct to vaccination and are effective when administered as treatment and when used for chemoprophylaxis after an exposure to influenza virus. Oseltamivir and zanamivir are the only antiviral medications recommended for use in the United States. Amantadine or rimantidine should not be used for the treatment or prevention of influenza in the United States until evidence of susceptibility to these antiviral medications has been reestablished among circulating influenza A viruses.
The efficacy (i.e., prevention of illness among vaccinated persons in controlled trials) and effectiveness (i.e., prevention of illness in vaccinated populations) of influenza vaccines depend in part on the age and immunocompetence of the vaccine recipient, the degree of similarity between the viruses in the vaccine and those in circulation, and the outcome being measured. Influenza vaccine efficacy and effectiveness studies have used multiple possible outcome measures, including the prevention of medically attended acute respiratory illness (MAARI), prevention of laboratory-confirmed influenza virus illness, prevention of influenza or pneumonia-associated hospitalizations or deaths, or prevention of seroconversion to circulating influenza virus strains.
Efficacy or effectiveness for more specific outcomes such as laboratory-confirmed influenza typically will be higher than for less specific outcomes such as MAARI because the causes of MAARI include infections with other pathogens that influenza vaccination would not be expected to prevent. Observational studies that compare less-specific outcomes among vaccinated populations to those among unvaccinated populations are subject to biases that are difficult to control for during analyses. For example, an observational study that determines that influenza vaccination reduces overall mortality might be biased if healthier persons in the study are more likely to be vaccinated. Randomized controlled trials that measure laboratory-confirmed influenza virus infections as the outcome are the most persuasive evidence of vaccine efficacy, but such trials cannot be conducted ethically among groups recommended to receive vaccine annually.
Both LAIV and TIV contain strains of influenza viruses that are antigenically equivalent to the annually recommended strains: one influenza A (H3N2) virus, one influenza A (H1N1) virus, and one influenza B virus. Each year, one or more virus strains in the vaccine might be changed on the basis of global surveillance for influenza viruses and the emergence and spread of new strains. All three vaccine virus strains were changed for the recommended vaccine for the 2008-09 influenza season, compared with the 2007-08 season.
During the preparation of TIV, the vaccine viruses are made noninfectious (i.e., inactivated or killed). Only subvirion and purified surface antigen preparations of TIV (often referred to as “split” and subunit vaccines, respectively) are available in the United States. TIV contains killed viruses and thus cannot cause influenza. LAIV contains live, attenuated viruses that have the potential to cause mild signs or symptoms such as runny nose, nasal congestion, fever or sore throat. LAIV is administered intranasally by sprayer, whereas TIV is administered intramuscularly by injection. LAW is licensed for use among nonpregnant persons aged 2-49 years; safety has not been established in persons with underlying medical conditions that confer a higher risk of influenza complications. TIV is licensed for use among persons aged >6 months, including those who are healthy and those with chronic medical conditions. LAW is generally regarded as more efficacious and effective than TIV.
In many populations, there remains a need for alternatives to TIV and LAW, and a need for adjunctive prophylactic or therapeutic regimens for the prevention and/or treatment of Influenza.
Pregnant Women and Neonates—
Pregnant women have protective levels of anti-influenza antibodies after vaccination. Passive transfer of anti-influenza antibodies that might provide protection from vaccinated women to neonates has been reported. A retrospective, clinic-based study conducted during 1998-2003 documented a non-significant trend towards fewer episodes of MAARI during one influenza season among vaccinated pregnant women compared with unvaccinated pregnant women and substantially fewer episodes of MAARI during the peak influenza season. However, a retrospective study conducted during 1997-2002 that used clinical records data did not indicate a reduction in ILI among vaccinated pregnant women or their infants. In another study conducted during 1995-2001, medical visits for respiratory illness among the infants were not substantially reduced. However, studies of influenza vaccine effectiveness among pregnant women have not included specific outcomes such as laboratory-confirmed influenza in women or their infants.
Elderly Population—
Adults aged >65 years typically have a diminished immune response to influenza vaccination compared with young healthy adults, suggesting that immunity might be of shorter duration (although still extending through one influenza season). However, a review of the published literature concluded that no clear evidence existed that immunity declined more rapidly in the elderly. Infections among the vaccinated elderly might be associated with an age-related reduction in ability to respond to vaccination rather than reduced duration of immunity. The only randomized controlled trial among community-dwelling persons aged >60 years reported a vaccine efficacy of 58% against influenza respiratory illness during a season when the vaccine strains were considered to be well-matched to circulating strains, but indicated that efficacy was lower among those aged >70 years. Influenza vaccine effectiveness in preventing MAARI among the elderly in nursing homes has been estimated at 20%-40%, and reported outbreaks among well-vaccinated nursing home populations have suggested that vaccination might not have any significant effectiveness when circulating strains are drifted from vaccine strains. In contrast, some studies have indicated that vaccination can be up to 80% effective in preventing influenza-related death. Among elderly persons not living in nursing homes or similar chronic-care facilities, influenza vaccine is 27%-70% effective in preventing hospitalization for pneumonia and influenza. Influenza vaccination reduces the frequency of secondary complications and reduces the risk for influenza-related hospitalization and death among community-dwelling adults aged >65 years with and without high-risk medical conditions (e.g., heart disease and diabetes). However, studies demonstrating large reductions in hospitalizations and deaths among the vaccinated elderly have been conducted using medical record databases and have not measured reductions in laboratory-confirmed influenza illness. These studies have been challenged because of concerns that they have not adequately controlled for differences in the propensity for healthier persons to be more likely than less healthy persons to receive vaccination.
HIV Compromised Individuals—
TIV produces adequate antibody concentrations against influenza among vaccinated HIV-infected persons who have minimal AIDS-related symptoms and normal or near-normal CD4+ T-lymphocyte cell counts. Among persons who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, TIV might not induce protective antibody titers; a second dose of vaccine does not improve the immune response in these persons. A randomized, placebo-controlled trial determined that TIV was highly effective in preventing symptomatic, laboratory-confirmed influenza virus infection among HIV-infected persons with a mean of 400 CD4+ T-lymphocyte cells/mm3; however, a limited number of persons with CD4+ T-lymphocyte cell counts of <200 were included in that study. A nonrandomized study of HIV-infected persons determined that influenza vaccination was most effective among persons with >100 CD4+ cells and among those with <30,000 viral copies of HIV type-1/mL.
Transplant Recipients—
On the basis of certain small studies, immunogenicity for persons with solid organ transplants varies according to transplant type. Among persons with kidney or heart transplants, the proportion that developed seroprotective antibody concentrations was similar or slightly reduced compared with healthy persons. However, a study among persons with liver transplants indicated reduced immunologic responses to influenza vaccination, especially if vaccination occurred within the 4 months after the transplant procedure.
Other Medical Conditions—
persons with underlying medical conditions including asthma, reactive airways disease, or other chronic disorders of the pulmonary or cardiovascular systems; metabolic diseases such as diabetes, renal dysfunction, and hemoglobinopathies; or known or suspected immunodeficiency diseases or immunosuppressed states should not be vaccinated with LAIV. In addition children or adolescents receiving aspirin or other salicylates should not be vaccinated with a LAIV because of the association of Reye syndrome and salicylates with wild-type influenza virus infection. Individuals with acute febrile illness should not be vaccinated with TIV or LAIV.
Pediatric Chronic Medical Conditions—
Among children with high-risk medical conditions, one study of 52 children aged 6 months-3 years reported fever among 27% and irritability and insomnia among 25% (113); and a study among 33 children aged 6-18 months reported that one child had irritability and one had a fever and seizure after vaccination. No placebo comparison group was used in these studies.
Hypersensitivity and Allergic Reactions—
Immediate and presumably allergic reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) occur rarely after influenza vaccination. These reactions probably result from hypersensitivity to certain vaccine components; the majority of reactions probably are caused by residual egg protein. Although influenza vaccines contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Manufacturers use a variety of different compounds to inactivate influenza viruses and add antibiotics to prevent bacterial contamination. Persons who have experienced hives or swelling of the lips or tongue, or who have experienced acute respiratory distress or who collapse after eating eggs, must consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma related to egg exposure or other allergic responses to egg protein, also might be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician before vaccination must be considered. Hypersensitivity reactions to other vaccine components can occur but are rare. Although exposure to vaccines containing thimerosal can lead to hypersensitivity, the majority of patients do not have reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity. When reported, hypersensitivity to thimerosal typically has consisted of local delayed hypersensitivity reactions.
Guillain-Barré Syndrome—
The annual incidence of Guillain-Barré Syndrome (GBS) is 10-20 cases per 1 million adults. Substantial evidence exists that multiple infectious illnesses, most notably Campylobacter jejuni gastrointestinal infections and upper respiratory tract infections, are associated with GBS. The 1976 swine influenza vaccine was associated with an increased frequency of GBS, estimated at one additional case of GBS per 100,000 persons vaccinated. The risk for influenza vaccine-associated GBS was higher among persons aged >25 years than among persons aged <25 years. However, obtaining strong epidemiologic evidence for a possible small increase in risk for a rare condition with multiple causes is difficult, and no evidence exists for a consistent causal relation between subsequent vaccines prepared from other influenza viruses and GBS.
None of the studies conducted using influenza vaccines other than the 1976 swine influenza vaccine have demonstrated a substantial increase in GBS associated with influenza vaccines. During three of four influenza seasons studied during 1977-1991, the overall relative risk estimates for GBS after influenza vaccination were not statistically significant in any of these studies. However, in a study of the 1992-93 and 1993-94 seasons, the overall relative risk for GBS was 1.7 (CI=1.0-2.8; p=0.04) during the 6 weeks after vaccination, representing approximately one additional case of GBS per 1 million persons vaccinated; the combined number of GBS cases peaked 2 weeks after vaccination. Results of a study that examined health-care data from Ontario, Canada, during 1992-2004 demonstrated a small but statistically significant temporal association between receiving influenza vaccination and subsequent hospital admission for GBS. However, no increase in cases of GBS at the population level was reported after introduction of a mass public influenza vaccination program in Ontario beginning in 2000. Data from VAERS have documented decreased reporting of GBS occurring after vaccination across age groups over time, despite overall increased reporting of other, non-GBS conditions occurring after administration of influenza vaccine. Cases of GBS after influenza virus infection have been reported, but no other epidemiologic studies have documented such an association. Recently published data from the United Kingdom's General Practice Research Database (GPRD) found influenza vaccine to be protective against GBS, although it is unclear if this was associated with protection against influenza or confounding because of a “healthy vaccine” (e.g., healthier persons might be more likely to be vaccinated and are lower risk for GBS). A separate GPRD analysis found no association between vaccination and GBS over a 9 year period; only three cases of GBS occurred within 6 weeks after influenza vaccine.
It is not known if GBS is a side effect of influenza vaccines other than 1976 swine influenza vaccine; the estimated risk for GBS (on the basis of the few studies that have demonstrated an association between vaccination and GBS) is low (i.e., approximately one additional case per 1 million persons vaccinated). It has been deemed by the CDC and others that the potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death substantially outweigh these estimates of risk for vaccine-associated GBS. No evidence indicates that the case fatality ratio for GBS differs among vaccinated persons and those not vaccinated
The incidence of GBS among the general population is low, but persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS when injected with TIV influenza vaccine than persons without such a history. Thus, the likelihood of coincidentally experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is unknown. However, avoiding vaccinating persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within 6 weeks after a previous influenza vaccination is often taken as a prudent as a precaution. As an alternative, physicians use influenza antiviral chemoprophylaxis for these persons. Although data are limited, the established benefits of influenza vaccination might outweigh the risks for many persons who have a history of GBS and who are also at high risk for severe complications from influenza.
Viral Shedding—
Available data indicates that both children and adults vaccinated with LAIV can shed vaccine viruses after vaccination, although in lower amounts than occur typically with shedding of wild-type influenza viruses. In rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated persons. However, serious illnesses have not been reported among unvaccinated persons who have been infected inadvertently with vaccine viruses.
One study of children aged 8-36 months in a child care center assessed transmissibility of vaccine viruses from 98 vaccinated to 99 unvaccinated subjects; 80% of vaccine recipients shed one or more virus strains (mean duration: 7.6 days). One influenza type B vaccine strain isolate was recovered from a placebo recipient and was confirmed to be vaccine-type virus. The type B isolate retained the cold-adapted, temperature-sensitive, attenuated phenotype, and it possessed the same genetic sequence as a virus shed from a vaccine recipient who was in the same play group. The placebo recipient from whom the influenza type B vaccine strain was isolated had symptoms of a mild upper respiratory illness but did not experience any serious clinical events. The estimated probability of acquiring vaccine virus after close contact with a single LAIV recipient in this child care population was 0.6%-2.4%.
Studies assessing whether vaccine viruses are shed have been based on viral cultures or PCR detection of vaccine viruses in nasal aspirates from persons who have received LAIV. One study of 20 healthy vaccinated adults aged 18-49 years demonstrated that the majority of shedding occurred within the first 3 days after vaccination, although the vaccine virus was detected in one subject on day 7 after vaccine receipt. Duration or type of symptoms associated with receipt of LAIV did not correlate with detection of vaccine viruses in nasal aspirates. Another study in 14 healthy adults aged 18-49 years indicated that 50% of these adults had viral antigen detected by direct immunofluorescence or rapid antigen tests within 7 days of vaccination. The majority of samples with detectable virus were collected on day 2 or 3. Vaccine strain virus was detected from nasal secretions in one (2%) of 57 HIV-infected adults who received LAIV, none of 54 HIV-negative participants (256), and three (13%) of 23 HIV-infected children compared with seven (28%) of 25 children who were not HIV-infected. No participants in these studies had detectable virus beyond 10 days after receipt of LAIV. The possibility of person-to-person transmission of vaccine viruses was not assessed in these studies.
LAIV Side Effects—
In a subset of healthy children aged 60-71 months from one clinical trial (233), certain signs and symptoms were reported more often after the first dose among LAIV recipients (n=214) than among placebo recipients (n=95), including runny nose (48% and 44%, respectively); headache (18% and 12%, respectively); vomiting (5% and 3%, respectively); and myalgias (6% and 4%, respectively). However, these differences were not statistically significant. In other trials, signs and symptoms reported after LAIV administration have included runny nose or nasal congestion (20%-75%), headache (2%-46%), fever (0-26%), vomiting (3%-13%), abdominal pain (2%), and myalgias (0-21%). These symptoms were associated more often with the first dose and were self-limited.
In a randomized trial published in 2007, LAIV and TIV were compared among children aged 6-59 months. Children with medically diagnosed or treated wheezing within 42 days before enrollment, or a history of severe asthma, were excluded from this study. Among children aged 24-59 months who received LAIV, the rate of medically significant wheezing, using a pre-specified definition, was not greater compared with those who received TIV; wheezing was observed more frequently among younger LAW recipients in this study. In a previous randomized placebo-controlled safety trial among children aged 12 months-17 years without a history of asthma by parental report, an elevated risk for asthma events (RR=4.06, CI=1.29-17.86) was documented among 728 children aged 18-35 months who received LAIV. Of the 16 children with asthma-related events in this study, seven had a history of asthma on the basis of subsequent medical record review. None required hospitalization, and elevated risks for asthma were not observed in other age groups.
Among adults aged 19-49, runny nose or nasal congestion (28%-78%), headache (16%-44%), and sore throat (15%-27%) have been reported more often among vaccine recipients than placebo recipients. In one clinical trial among a subset of healthy adults aged 18-49 years, signs and symptoms reported more frequently among LAW recipients (n=2,548) than placebo recipients (n=1,290) within 7 days after each dose included cough (14% and 11%, respectively); runny nose (45% and 27%, respectively); sore throat (28% and 17%, respectively); chills (9% and 6%, respectively); and tiredness/weakness (26% and 22%, respectively).
There are additional reasons why it would be useful to have alternative or adjunctive prophylactic and/or therapeutic options for the prevention and/or treatment of Influenza, as discussed below.
Challenging Prediction of Virus Strains—
Manufacturing trivalent influenza virus vaccines is a challenging process that takes 6-8 months to complete. This manufacturing timeframe requires that influenza vaccine strains for influenza vaccines used in the United States must be selected in February of each year by the FDA to allow time for manufacturers to prepare vaccines for the next influenza season. Vaccine strain selections are based on global viral surveillance data that is used to identify trends in antigenic changes among circulating influenza viruses and the availability of suitable vaccine virus candidates.
Vaccination can provide reduced but substantial cross-protection against drifted strains in some seasons, including reductions in severe outcomes such as hospitalization. Usually one or more circulating viruses with antigenic changes compared with the vaccine strains are identified in each influenza season. However, assessment of the clinical effectiveness of influenza vaccines cannot be determined solely by laboratory evaluation of the degree of antigenic match between vaccine and circulating strains. In some influenza seasons, circulating influenza viruses with significant antigenic differences predominate and, compared with seasons when vaccine and circulating strains are well-matched, reductions in vaccine effectiveness are sometimes observed. However, even during years when vaccine strains were not antigenically well matched to circulating strains, substantial protection has been observed against severe outcomes, presumably because of vaccine-induced cross-reacting antibodies. For example, in one study conducted during an influenza season (2003-04) when the predominant circulating strain was an influenza A (H3N2) virus that was antigenically different from that season's vaccine strain, effectiveness among persons aged 50-64 years against laboratory-confirmed influenza illness was 60% among healthy persons and 48% among persons with medical conditions that increase risk for influenza complications. An interim, within-season analysis during the 2007-08 influenza season indicated that vaccine effectiveness was 44% overall, 54% among healthy persons aged 5-49 years, and 58% against influenza A, despite the finding that viruses circulating in the study area were predominately a drifted influenza A H3N2 and a influenza B strain from a different lineage compared with vaccine strains. Among children, both TIV and LAW provide protection against infection even in seasons when vaccines and circulating strains are not well matched. Vaccine effectiveness against ILI was 49%-69% in two observational studies, and 49% against medically attended, laboratory-confirmed influenza in a case-control study conducted among young children during the 2003-04 influenza season, when a drifted influenza A H3N2 strain predominated, based on viral surveillance data. However, the FDA admits that continued improvements in collecting representative circulating viruses and use surveillance data to forecast antigenic drift are needed. Shortening manufacturing time to increase the time to identify good vaccine candidate strains from among the most recent circulating strains also is also important. Data from multiple seasons and collected in a consistent manner are needed to better understand vaccine effectiveness during seasons when circulating and vaccine virus strains are not well-matched.
Vaccine Coverage—
vaccination coverage of the population is influenced by a multitude of factors including vaccine supply delays and shortages, changes in influenza vaccination recommendations and target groups for vaccination, reimbursement rates for vaccine and vaccine administration, and other factors related to vaccination coverage among adults and children. Production issues coupled with the requirement to forecast appropriate influenza types and antigens have caused severe shortfalls in vaccine availability, for example in the years 2004-05 an American company, Chiron, had their operating license suspended by British officials following problems at their manufacturing plant in Liverpool, England. Due to contamination in a batch of vaccines intended for American market they were unable to supply their flu vaccine, Fluvirin. Fluvirin made up approximately 50% of America's expected demand for the winter flu season.
Because of the inherent risk factors and the reluctance of individuals to accept those risks, many at risk groups have very low vaccination coverage. For example vaccine coverage among pregnant women has not increased significantly during the preceding decade. Only 12% and 13% of pregnant women participating in the 2006 and 2007 NHIS reported vaccination during the 2005-06 and 2006-07 seasons, respectively, excluding pregnant women who reported diabetes, heart disease, lung disease, and other selected high-risk conditions. In a study of influenza vaccine acceptance by pregnant women, 71% of those who were offered the vaccine chose to be vaccinated. However, a 1999 survey of obstetricians and gynecologists determined that only 39% administered influenza vaccine to obstetric patients in their practices, although 86% agreed that pregnant women's risk for influenza-related morbidity and mortality increases during the last two trimesters.
Drug Resistance—
Viral neuraminidase is an enzyme on the surface of influenza viruses that enables the virus to be released from the host cell. Drugs that inhibit neuraminidase are often used to treat influenza. Neuraminidase has been targeted in structure-based enzyme inhibitor design programmes that have resulted in the production of two drugs, zanamivir (Relenza) and oseltamivir (Tamiflu). Administration of neuraminidase inhibitors is a treatment that limits the severity and spread of viral infections. Neuraminidase inhibitors are useful for combating influenza infection: zanamivir, administered by inhalation; oseltamivir, administered orally; and under research is peramivir administered parenterally, that is through intravenous or intramuscular injection.
On Feb. 27, 2005, a 14-year-old Vietnamese girl was documented to be carrying an H5N1 influenza virus strain that was resistant to the drug oseltamivir. The drug is used to treat patients that have contracted influenza. However, the Vietnamese girl who had received a prophylaxis dose (75 mg once a day) was found to be non-responsive to the medication. In growing fears of a global avian flu pandemic, scientists began to look for a cause of resistance to the Tamiflu medication. The cause was determined to be a histidine-to-tryosine (amino acid) substitution at position 274 in its neuraminidase protein.